The purpose of this project is to investigate molecular mechanisms involved in the response of cells to hyperthermia. We will concentrate on determining the effect of clinically relevant hyperthermia doses an the functions of membrane enzyme systems involved in transmembrane signaling. Our preliminary data indicates that hyperthermia produces rapid and profound stimulation of the 3 major such systems. These are the adenylate cyclase, phospholipase C and phospholipase A2 systems. As these signaling systems are intimately involved in regulating all of the major functions of cells (proliferation, differentiation, metabolism, etc.) Their stimulation by hyperthermia may be highly significant. We will investigate the hypothesis that activation of transmembrane signal pathways generates cascade responses at the plasma membrane. These cascade responses may then be involved in mediating thermal cell killing, inducing thermotolerance and modulating tumor blood flow and cellular radiosensitivity. We will additionally examine the hypothesis that a common component of all signal transduction systems, the guanine nucleotide binding protein, constitutes a universal target for hyperthermia. We aim to test the possibility that these proteins may serve as transducers of the physical effects of hyperthermia just as they transduce the chemical messages of hormones and other signalling agonists.